ArticleMolecular metabolism2020
Pharmacological antagonism of the incretin system protects against diet-induced obesity.
Article in Molecular metabolism, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 63 citations in OpenAlex.
- GIPR signaling modulates PYY-induced hypophagia and malaise in rodents.Molecular metabolism · 2026Article
- GIP receptor agonism suppresses inflammation-induced aversion and food intake via distinct circuits.Cell reports · 2026Article
- GLP-1 physiology and pharmacology along the gut-brain axis.The Journal of clinical investigation · 2026Review
- α cells use both PC1/3 and PC2 to process proglucagon peptides and control insulin secretion.Science advances · 2025Article
- GIP receptor agonism suppresses inflammation-induced aversion and food intake via distinct circuits.bioRxiv : the preprint server for biology · 2025Article
- Review
- GIP Receptor Antagonists in the Pharmacotherapy of Obesity: Physiologic, Genetic, and Clinical Rationale.Diabetes · 2025Review
- Glucose-Dependent Insulinotropic Polypeptide in Incretin Physiology: Role in Health and Disease.Endocrine reviews · 2025Review
- The Premise of the Paradox: Examining the Evidence That Motivated GIPR Agonist and Antagonist Drug Development Programs.Journal of clinical medicine · 2025Review
- The role of GIPR in food intake control.Frontiers in endocrinology · 2025Review
- Activation of Gs signaling in mouse enteroendocrine K cells greatly improves obesity- and diabetes-related metabolic deficits.The Journal of clinical investigation · 2024Article
- Adipose Tissue: A Novel Target of the Incretin Axis? A Paradigm Shift in Obesity-Linked Insulin Resistance.International journal of molecular sciences · 2024Review
- Review
- Advances in the Management of Diabetes and Overweight using Incretin-based Pharmacotherapies.Current diabetes reviews · 2024Review
- Relevance and consequence of chronic inflammation for obesity development.Molecular and cellular pediatrics · 2023Review
- GIPR/GLP-1R dual agonist therapies for diabetes and weight loss-chemistry, physiology, and clinical applications.Cell metabolism · 2023Review
- Beyond the pancreas: contrasting cardiometabolic actions of GIP and GLP1.Nature reviews. Endocrinology · 2023Review
- Nephroprotective Properties of the Glucose-Dependent Insulinotropic Polypeptide (GIP) and Glucagon-like Peptide-1 (GLP-1) Receptor Agonists.Biomedicines · 2022Review
- Hypertension Related to Obesity: Pathogenesis, Characteristics and Factors for Control.International journal of molecular sciences · 2022Review
- Roles of glucose-dependent insulinotropic polypeptide in diet-induced obesity.Journal of diabetes investigation · 2022Review
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
Abstract
objectiveGlucose-dependent insulinotropic polypeptide is an intestinally derived hormone that is essential for normal metabolic regulation. Loss of the GIP receptor (GIPR) through genetic elimination or pharmacological antagonism reduces body weight and adiposity in the context of nutrient excess. Interrupting GIPR signaling also enhances the sensitivity of the receptor for the other incretin peptide, glucagon-like peptide 1 (GLP-1). The role of GLP-1 compensation in loss of GIPR signaling to protect against obesity has not been directly tested.
methodsWe blocked the GIPR and GLP-1R with specific antibodies, alone and in combination, in healthy and diet-induced obese (DIO) mice. The primary outcome measure of these interventions was the effect on body weight and composition.
resultsAntagonism of either the GIPR or GLP-1R system reduced food intake and weight gain during high-fat feeding and enhanced sensitivity to the alternative incretin signaling system. Combined antagonism of both GIPR and GLP-1R produced additive effects to mitigate DIO. Acute pharmacological studies using GIPR and GLP-1R agonists demonstrated both peptides reduced food intake, which was prevented by co-administration of the respective antagonists.
conclusionsDisruption of either axis of the incretin system protects against diet-induced obesity in mice. However, combined antagonism of both GIPR and GLP-1R produced additional protection against diet-induced obesity, suggesting additional factors beyond compensation by the complementary incretin axis. While antagonizing the GLP-1 system decreases weight gain, GLP-1R agonists are used clinically to target obesity. Hence, the phenotype arising from loss of function of GLP-1R does not implicate GLP-1 as an obesogenic hormone. By extension, caution is warranted in labeling GIP as an obesogenic hormone based on loss-of-function studies.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.